The long-term objective of this project is to advance the understanding of the pathophysiology of type 2 diabetes mellitus and provide the opportunity for Dr. Cavaghan to develop the skills required of an independent investigator. Dr. Cavaghan has completed subspecialty training in Endocrinology and has carried out several clinical research projects under the supervision of Dr. Kenneth S. Polonsky, her proposed sponsor, and in collaboration with other investigators at the University of Chicago. These projects have resulted in several publications and required that the applicant master skills in clinical design, precise execution of the study protocols, direct performance of a precise and ultrasensitive insulin assay, and in statistical data analysis and interpretation. Dr. Cavaghan is currently pursuing a career in clinical research in the field of diabetes, focusing on the physiology of beta cell dysfunction in type 2 diabetes. In order to develop further as an investigator, more experience is required. The University of Chicago has a long-standing commitment to both basic and clinical research and has a very active GCRC, where all of the clinical protocols will be performed. This project will provide the additional opportunity for Dr. Cavaghan to systematically and thoroughly study the specific question of the role of free fatty acids (FFAs) in the pathophysiology of beta cell dysfunction in diabetes. Diabetes is thought to occur when the demands of insulin resistance are superimposed on a genetic predisposition for the disease. FFAs are elevated in states of insulin resistance, but the effects of elevated FFAs on insulin secretion in humans have not been studied systematically. This project will test the hypotheses that elevated FFAs will 1) impair the ability of the beta cell to detect and respond to slow changes in plasma glucose, 2) acutely augment rapid pulsatile insulin release in response to glucose, 3) blunt the glucose-insulin dose response relationship after a 24-hour exposure, 4) abolish the glucose priming effect on the glucose-insulin dose response curve, and 5) impair the acute insulin response to a glucose bolus when compared to the degree of insulin resistance induced. Finally, it will examine the effect of pretreatment with the troglitazone on the ability of the beta cell to detect and respond to slow changes in plasma glucose even when FFAs are elevated. Studies will be performed in obese humans with and without impaired glucose tolerance. Beta cell function will be assessed during an oscillatory glucose infusion, rapid pulses of intravenous glucose, a graded intravenous glucose infusion, and a frequently-sampled intravenous glucose tolerance test. Subjects will be studied with and without an intralipid/heparin infusion for the purpose of elevating FFAs. It is expected that these studies will provide valuable insight into the role of FFAs in the pathophysiology of beta cell dysfunction in type 2 diabetes and inform future direction into therapeutic options for the prevention and treatment of this disease.